Disease relevance of Nfatc2

• Nfatc2(-/-) Nfatc4(-/-) mice are also protected from diet-induced obesity [1].
• In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells [2].
• Here we report that NFATp is also expressed in the rat PC12 pheochromocytoma cell line and in the murine nervous system [3].
• Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts [4].
• Recently, the calcium-activated phosphatase calcineurin (PP2B) and the family of transcription factors known as NFAT have been implicated in the regulation of myocyte hypertrophy and fiber type specificity [5].
• Combined, these results reveal a major role for the NFATc2 transcription factor in pathological cardiac remodeling and heart failure [6].

High impact information on Nfatc2

• We show that NFATc2 has pro migratory and pro invasive capabilities in breast cancer cells [7][8].
• Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs [9] .
• We show that the initiation of heart valve morphogenesis in mice requires calcineurin/NFAT to repress VEGF expression in the myocardium underlying the site of prospective valve formation [10].
• Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex [11].
• Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells [12].
• Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts [13].

Biological context of Nfatc2

• In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts [13].
• Nuclear factor of activated T cells (NFAT) is a family of four related transcription factors implicated in cytokine and early response gene expression in activated lymphocytes [14].
• Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development [15].
• These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response [2].
• Nuclear factor of activated T cells (NFAT) is a critical regulator of early gene transcription in response to TCR-mediated signals [15].

Anatomical context of Nfatc2

• Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression [13].
• The NF-AT complex consists of two components: NF-ATp, which pre-exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP-1 component whose induction is dependent upon activation of protein kinase C (PKC) [16].
• The widely used immunosuppressant agents cyclosporin and FK506 are thought to antagonize the immune response by directly inhibiting calcineurin-NFAT signal transduction in lymphocytes [17].
• It has been reported that both NFAT1 and NFATx are required to maintain the homeostasis of the immune system [18].
• In an in vivo model of allergic inflammation, the accumulation of eosinophils and levels of serum immunoglobulin E were increased in NFAT1 -/- mice [19].

Associations of Nfatc2 with chemical compounds

• NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix [13].
• Covalent modification of NIP45 by arginine methylation is an important mechanism of regulating the expression of NFAT-dependent cytokine genes [20].
• A dominant negative NFAT molecule attenuates LPS- and IFN-gamma-activated endogenous IL-12 p40 mRNA expression [21].
• Further, mutation of the threonine residue in this sequence to cysteine, as in Rel proteins, confers on NFATp a sensitivity to sulfhydryl modification similar to that of Rel family proteins [22].
• One specific short sequence in NFATp (RAHYETEG), located near the NH2 terminus of the DNA-binding domain, resembles a highly conserved sequence (RFRYxCEG) that is located near the NH2 terminus of the Rel homology region and that has been implicated in DNA binding by Rel family proteins [22].
• These results support the view that high NFAT activity is necessary for TNF-alpha and IL-13 promoter induction in MC, irrespective of whether NFATc2 or NFATc1 or a combination of both is present [23].

Physical interactions of Nfatc2

• Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter [24].
• Mutational analysis demonstrates that the residues in this sequence that are identical in NFATp and Rel family proteins contribute to DNA binding by NFATp [22].
• Electrophoretic mobility shift and supershift assays revealed the presence of a nuclear factor of activated T cells (NFAT) binding site in the utrophin A promoter [25].
• NFAT binds to a region of the IL-2 enhancer that has been defined as a TCR response element (ARRE-2), and is induced in response to increases in intracellular calcium, stimulation of PKC, or triggering of the TCR [26].
• We have previously reported that NFAT DNA-binding activity significantly decreases in the thymus during glucocorticoid-induced apoptosis [27].

Regulatory relationships of Nfatc2

• Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells [28].
• These results suggest that IFN-gamma production by T cells is regulated by NFAT1, most likely at the level of gene transcription [29].
• Whereas the binding of NFAT-1 and Octamer factors enhance the activity of the Il-4 promoter, the binding of HMG I(Y) suppresses its activity and, therefore, appears to be involved in the suppression of Il-4 transcription in resting T lymphocytes [24].
• The activity NFAT proteins is regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a target for inhibition by CsA and FK506 [30].
• A mechanism underlying this effect was suggested by the observation that JNK directly regulated nuclear factor of activated T-cell (NFAT) activation in culture and in transgenic mice containing an NFAT-dependent luciferase reporter [31].

Other interactions of Nfatc2

• NFAT and Osterix cooperatively regulate bone formation [13].
• Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice [2].
• Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation [32].
• Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-gamma production in vivo [29].
• PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT [33].

Analytical, diagnostic and therapeutic context of Nfatc2

• The molecular cloning of NFATp should allow detailed analysis of a T cell transcription factor that is central to initiation of the immune response [28].
• DNA binding of NFAT and ICSBP is demonstrated on the endogenous promoter by chromatin immunoprecipitation [21].
• This is supported by our gel mobility shift assays indicating that calcineurin and/or PMA-inducible NF-ATp, OAP40, and AP-1, but not calcineurin-independent Oct-2, are repressed in anergic spleen T cells upon restimulation with SEB [34].
• In order to elucidate the role of NF-ATp, one of the most prominent members of family of NF-AT transcription factors in peripheral T lymphocytes, in T cell activation and differentiation we created NF-ATp-deficient mice by gene targeting [35].
• B-cell proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to B-cell receptor (BCR) ligation were all impaired [36].

References